Momelotinib is a wild-type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2V617F inhibitor approved for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis or secondary myelofibrosis [post-polycythemia vera (PV) and post-essential thrombocythemia (ET)], in adults with anemia. Momelotinib and its major metabolite, M21, additionally inhibit activin A receptor type 1 (ACVR1), which lowers hepcidin levels and increases iron availability, resulting in increased red blood cell production. The efficacy of momelotinib was established based on reduced constitutional symptoms, spleen volume response, and transfusion independence, compared to danazol.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Emetic Risk
-Minimal/Low
-Administer prn antiemetics as necessary.
Route-Specific Administration
Oral Administration
-Momelotinib may be taken with or without food.
-If a dose is missed, skip the missed dose and take the next scheduled dose the following day.
Oral Solid Formulations
-Swallow momelotinib tablets whole; do not cut, crush, or chew.
Infection occurred in 38% of patients treated with momelotinib across clinical trials. Excluding opportunistic infections, bacterial infections occurred in 15% to 21% (grade 3 or higher, 8%), viral infections in 6% to 12% (grade 3 and higher, 5% or less), and renal and urinary tract infections in (6% to 12%; grade 3 or higher, 1% to 2%) of momelotinib-treated patients in 2 clinical trials; fungal infection occurred in less than 5% of anemia patients in these trials. Additionally, grade 3 or higher pneumonia was reported in 8% of patients 1 clinical trial. Delay the initiation of therapy until active infections have resolved. Monitor patients for signs and symptoms of infection and promptly initiate appropriate therapy.
Hepatitis B exacerbation by way of viral load (HBV-DNA titer) increases, with or without associated transaminitis, has occurred in patients with chronic hepatitis B (HBV) treated with Janus Kinase (JAK) inhibitors including momelotinib. Check hepatitis B serologies in patients with HBV infection prior to initiation of momelotinib therapy and monitor according to clinical HBV guidelines. If either the hepatitis B surface antigen (HBsAg) and/or antibody to hepatitis B core antigen (anti-HBc antibody) is positive, consider consultation with a hepatologist regarding monitoring for reactivation versus prophylactic HBV therapy. The effect of momelotinib on viral replication in patients with chronic HBV infection is unknown.
Thrombocytopenia (21% to 28%; grade 3 or higher, 11% to 22%) and neutropenia (grade 3 or higher, 5% or less) have been reported in patients treated with momelotinib across clinical trials; 8% of patients treated with momelotinib had baseline platelet counts less than 50,000 cells/dL. Monitor complete blood counts at baseline and periodically during treatment, as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for patients who develop thrombocytopenia or neutropenia.
Elevated hepatic enzymes occurred in 10% to 11% (grade 3 or higher, 2% to 4%) of patients treated with momelotinib in 2 clinical trials. New or worsening increases in ALT or AST from baseline occurred in 23% to 24% of patients (grade 3 or 4, 1% and 0.5%) while new or worsening increases in total bilirubin (hyperbilirubinemia) from baseline occurred in 16%. Two patients with myelofibrosis who received at least one dose of momelotinib in clinical trials (n = 993) experienced reversible drug-induced liver injury. The median time to onset of transaminitis was 2 months; 75% of cases occurred within 4 months. Monitor liver function tests at baseline, every month for 6 months, and then periodically as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy is necessary for patients who develop hepatotoxicity.
Diarrhea (20% to 22%; grade 3 or higher, 1% or less), nausea (16% to 20%; grade 3 or higher, 2% or less), abdominal pain (13% to 18%; grade 3 or higher, 1%), and vomiting (8%; grade 3 or higher, 1% or less) were reported in patients treated with momelotinib in 2 clinical trials.
Grade 1 or 2 rash occurred in 6% to 12% of patients treated with momelotinib in 2 clinical trials; pruritus was reported in 11% (grade 3 or higher, 2%) of patients in 1 of these trials.
Bleeding occurred in 21% to 22% (grade 3 or higher, 1% to 2%) of patients treated with momelotinib in 2 clinical trials.
Fatigue occurred in 21% to 22% (grade 3 or higher, 2% or less) of patients treated with momelotinib in 2 clinical trials.
Dizziness occurred in 8% to 24% (grade 3 or higher, 1% to 2%) of patients treated with momelotinib in 2 clinical trials; serious cases of syncope were separately reported in 2% of momelotinib-treated patients in one of these trials. Headache occurred in 11% of patients who received momelotinib in 1 clinical trial.
Paresthesias were reported in 8% of patients treated with momelotinib in 2 clinical trials (grade 3 or higher, 1% or less). Neuralgia, peripheral neuropathy, peripheral motor neuropathy, and polyneuropathy were reported in less than 5% of patients who received momelotinib in these trials.
Grade 1 or 2 cough was reported in 8% to 14% of patients treated with momelotinib in 2 clinical trials.
Arrhythmias or arrhythmia exacerbation occurred in 5% to 8% of patients treated with momelotinib in 2 clinical trials (grade 3 or higher, 1% to 2%). Serious cases of heart failure occurred in 4% of patients who received momelotinib in 1 of these trials.
Fever occurred in 10% to 12% of patients treated with momelotinib in 2 clinical trials (grade 3 or higher, 1% to 2%).
Hypotension occurred in 14% of patients treated with momelotinib in a randomized clinical trial (grade 3 or higher, 2%).
Back pain (7%; grade 3 or higher, 1%) and extremity pain (12%) were reported in patients treated with momelotinib in a randomized clinical trial.
Grade 1 or 2 peripheral edema occurred in 11% of patients treated with momelotinib in a randomized clinical trial.
Serious cases of thrombosis occurred in 3% of patients treated with momelotinib in a randomized clinical trial.
Blurred vision occurred in less than 5% of patients treated with momelotinib in 2 randomized clinical trials.
Flushing occurred in less than 5% of patients treated with momelotinib in 2 randomized clinical trials.
Serious cases of acute kidney injury (renal failure) occurred in 3% of patients treated with momelotinib in a randomized clinical trial.
Serious infection has occurred in patients treated with momelotinib therapy. Delay the initiation of therapy until active infections have resolved. Monitor patients for signs and symptoms of infection and promptly initiate appropriate therapy.
Hepatitis B exacerbation by way of viral load (HBV-DNA titer) increases, with or without associated transaminitis, has occurred in patients with chronic hepatitis B (HBV) treated with Janus Kinase (JAK) inhibitors including momelotinib. Check hepatitis B serologies in patients with HBV infection prior to initiation of momelotinib therapy and monitor according to clinical HBV guidelines. If either the hepatitis B surface antigen (HBsAg) and/or antibody to hepatitis B core antigen (anti-HBc antibody) is positive, consider consultation with a hepatologist regarding monitoring for reactivation versus prophylactic HBV therapy. The effect of momelotinib on viral replication in patients with chronic HBV infection is unknown.
Thrombocytopenia and neutropenia have been reported in patients treated with momelotinib across clinical trials. Monitor complete blood counts at baseline and periodically during treatment, as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for patients who develop thrombocytopenia or neutropenia.
Do not start therapy in patients with uncontrolled acute or chronic hepatic disease until causes have been investigated and treated as clinically indicated. An initial dose reduction is required for patients with Child-Pugh C hepatic impairment. Monitor liver function tests at baseline, every month for 6 months, and then periodically as clinically indicated. An interruption of therapy, dose reduction, or discontinuation of therapy is necessary for patients who develop hepatotoxicity.
The risk of Major Adverse Cardiovascular Events (MACE) including cardiovascular death, myocardial infarction, and stroke was increased with the use of another JAK inhibitor compared with those treated with tumor necrosis factor (TNF) blockers in patients with rheumatoid arthritis. Consider the risks and benefits of therapy prior to initiating or continuing momelotinib therapy in patients with cardiovascular risk factors including smoking and cardiac disease. Educate patients of the symptoms of serious cardiovascular events and the steps to take if they occur.
The risk of thrombosis including deep venous thrombosis, pulmonary embolism, and arterial thrombosis was increased with the use of another JAK inhibitor compared with those treated with tumor necrosis factor (TNF) blockers in patients with rheumatoid arthritis. Evaluate patients with symptoms of thrombosis and treat appropriately.
The risk of a new primary malignancy including lymphoma and other malignancies excluding nonmelanoma skin cancer (NMSC) was increased with the use of another JAK inhibitor compared with those treated with tumor necrosis factor (TNF) blockers in patients with rheumatoid arthritis. Consider the risks and benefits of initiating or continuing momelotinib therapy in patients with a known malignancy other than successfully treated NMSC and patients who develop a malignancy.
Tobacco smoking increased the risk of developing a Major Cardiovascular Adverse Event (MACE) such as cardiovascular death, myocardial infarction, and stroke or a new primary malignancy including lymphoma and other malignancies (and excluding nonmelanoma skin cancer [NMSC]) with the use of another JAK inhibitor compared with those treated with tumor necrosis factor (TNF) blockers in patients with rheumatoid arthritis. Consider the risks and benefits of therapy prior to initiating or continuing momelotinib therapy in current or past smokers. Educate patients of the symptoms of serious cardiovascular events and the steps to take if they occur.
Pregnancy should be avoided by females of reproductive potential during momelotinib treatment and for at least 1 week after the last dose. Although there are no adequately controlled studies in pregnant women, momelotinib can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies at exposures lower than the expected exposure in patients receiving the recommended dose of 200 mg once daily. If treatment with momelotinib is unavoidable during pregnancy, it should only be used if the expected benefits to the mother outweigh the potential risks to the fetus. Women who are pregnant or who become pregnant while receiving momelotinib should be apprised of the potential hazard to the fetus. Embryofetal toxicity including embryonic death, soft tissue anomalies, skeletal variations, and lower mean fetal body weight occurred in the presence of maternal toxicity in an embryofetal development study where pregnant rats received momelotinib during organogenesis; skeletal variations were observed in the absence of maternal toxicity at exposures 3.5 times the exposure at the recommended human dose of 200 mg once daily; no developmental toxicity was observed at exposures equivalent to the recommended dose. In pregnant rabbits, momelotinib administration during organogenesis resulted in reduced fetal weight, delayed bone ossification, and an abortion at exposures less than the recommended human dose. When administered to pregnant rats from organogenesis through lactation, decreased pup body weight and embryo-lethality were observed at exposures approximately 2 times that expected with the recommended human dose.
Counsel patients about the reproductive risk and contraception requirements during momelotinib treatment. Momelotinib can be teratogenic if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 1 week after treatment with momelotinib. Females of reproductive potential should undergo pregnancy testing prior to initiation of momelotinib. Women who become pregnant while receiving momelotinib should be apprised of the potential hazard to the fetus. Although there are no data regarding the effect of momelotinib on human fertility, male and female infertility has been observed in animal studies.
Due to the potential for serious adverse reactions in nursing infants from momelotinib, advise women to discontinue breast-feeding during treatment and for at least 1 week after the final dose. It is not known whether momelotinib is present in human milk, although many drugs are excreted in human milk.
For the treatment of myelofibrosis:
-for the treatment of intermediate or high-risk primary or secondary (post-polycythemia vera and post-essential thrombocythemia) myelofibrosis, in adults with anemia:
NOTE: The FDA has designated momelotinib as an orphan drug for the treatment of myelofibrosis.
Oral dosage:
Adults: 200 mg orally once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. The primary endpoint of a 50% or more reduction in the Myelofibrosis Symptom Assessment Form total symptom score at week 24 was achieved in significantly more patients with symptomatic and anemic adults with myelofibrosis who had previously received JAK inhibitor therapy treated with momelotinib compared with those who received danazol (25% vs. 9%) in a multicenter, randomized, double-blind, phase 3 clinical trial (MOMENTUM); after 24 weeks of treatment on study, patients were switched to open-label treatment with momelotinib. Transfusion independence, defined as no transfusion or hemoglobin less than 8 g/dL between weeks 12 and 24 of therapy, occurred in 30% versus 20% of patients, respectively; 35% of patients in the momelotinib arm and 17% of patients in the danazol arm required no transfusions during the 24-week treatment period. Spleen volume was reduced by 25% or more in 39% of patients treated with momelotinib compared with 6% of those who received danazol; spleen volume was reduced by 35% or more in 22% and 3% of patients, respectively. In another multicenter, randomized, double-blind, phase 3 clinical trial, momelotinib treatment was noninferior to ruxolitinib for spleen response but not for symptom response in patients with high-risk, intermediate-2 risk, or symptomatic intermediate-1 risk JAK-naive myelofibrosis.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities
Neutropenia
-ANC less than 500 cells/dL: Hold momelotinib therapy. When the ANC recovers to at least 750 cells/dL, reduce the dose of momelotinib by 50 mg per day and resume therapy; may reinitiate therapy at 100 mg once daily if previously dosed at 100 mg. The dose may be escalated to the starting dosage as clinically appropriate. Discontinue momelotinib in patients unable to tolerate a dose of 100 mg PO once daily.
Thrombocytopenia
Baseline platelet counts 100,000 cells/dL or higher
-Platelet counts 20,000 to 49,999 cells/dL: Reduce the dose of momelotinib by 50 mg per day. The dose may be escalated to the starting dosage as clinically appropriate. Discontinue momelotinib in patients unable to tolerate a dose of 100 mg PO once daily.
-Platelet counts less than 20,000 cells/dL: Hold momelotinib therapy. When platelets recover to 50,000 cells/dL, reduce the dose of momelotinib by 50 mg per day and resume therapy; may reinitiate therapy at 100 mg once daily if previously dosed at 100 mg. The dose may be escalated to the starting dosage as clinically appropriate. Discontinue momelotinib in patients unable to tolerate a dose of 100 mg PO once daily.
Baseline platelet counts less than 100,000 cells/dL
-Platelet counts less than 20,000 cells/dL: Hold momelotinib therapy. When platelets recover to 50,000 cells/dL (or baseline if less than 50,000 cells/dL), reduce the dose of momelotinib by 50 mg per day and resume therapy; may reinitiate therapy at 100 mg once daily if previously dosed at 100 mg. The dose may be escalated to the starting dosage as clinically appropriate. Discontinue momelotinib in patients unable to tolerate a dose of 100 mg PO once daily.
Non-hematologic Toxicities
-Grade 3 or higher: Hold momelotinib therapy. When the toxicity recovers to grade 1 or less (or baseline if higher than grade 1), reduce the dose of momelotinib by 50 mg per day and resume therapy; may reinitiate therapy at 100 mg once daily if previously dosed at 100 mg. The dose may be escalated to the starting dosage as clinically appropriate. Discontinue momelotinib in patients unable to tolerate a dose of 100 mg PO once daily.
Maximum Dosage Limits:
-Adults
200 mg PO once daily.
-Geriatric
200 mg PO once daily.
-Adolescents
Safety and efficacy not established.
-Children
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Baseline Hepatic Impairment
-Mild to moderate hepatic impairment (Child-Pugh A or B): No dose adjustment is recommended.
-Severe hepatic impairment (Child-Pugh C): Reduce the starting dose of momelotinib to 150 mg PO once daily.
Treatment-Related Hepatotoxicity
-ALT/AST greater than 5 times the upper limit of normal (ULN) (or more than 5 times baseline if baseline is abnormal), and/or total bilirubin greater than 2 times ULN (or more than 2 times baseline, if baseline is abnormal): Hold momelotinib therapy. When ALT/AST recovers to 2 times ULN or less (or baseline) and total bilirubin recovers to 1.5 times ULN or less (or baseline), reduce the dose of momelotinib by 50 mg per day and resume therapy; may reinitiate therapy at 100 mg once daily if previously dosed at 100 mg. The dose may be escalated to the starting dosage as clinically appropriate. Discontinue momelotinib in patients unable to tolerate a dose of 100 mg PO once daily. If the ALT/AST increases above 5 times ULN for a second time, permanently discontinue momelotinib therapy.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with momelotinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and momelotinib is a BCRP inhibitor.
Alpelisib: (Major) Avoid coadministration of alpelisib with momelotinib due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and momelotinib is a BCRP inhibitor.
Amlodipine; Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with momelotinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP substrate; momelotinib is a BCRP inhibitor.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with clarithromycin is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; clarithromycin is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Asciminib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with asciminib is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; asciminib is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Atazanavir; Cobicistat: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; cobicistat is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Atorvastatin: (Moderate) Monitor for an increase in atorvastatin-related adverse reactions, including myopathy and rhabdomyolysis, if coadministration with momelotinib is necessary. Concomitant use may increase atorvastatin exposure. Atorvastatin is a BCRP substrate; momelotinib is a BCRP inhibitor.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with momelotinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and momelotinib is a BCRP inhibitor.
Clarithromycin: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with clarithromycin is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; clarithromycin is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Cobicistat: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; cobicistat is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Darolutamide: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with darolutamide is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; darolutamide is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Darunavir; Cobicistat: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; cobicistat is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with momelotinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and momelotinib is a BCRP inhibitor. (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; cobicistat is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with momelotinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and momelotinib is a BCRP inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with momelotinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and momelotinib is a BCRP inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with momelotinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and momelotinib is a BCRP inhibitor.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with momelotinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and momelotinib is a BCRP inhibitor.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with momelotinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and momelotinib is a BCRP inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with momelotinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and momelotinib is a BCRP inhibitor.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with elexacaftor is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; elexacaftor is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with momelotinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and momelotinib is a BCRP inhibitor. (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; cobicistat is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with momelotinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and momelotinib is a BCRP inhibitor. (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; cobicistat is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with momelotinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and momelotinib is a BCRP inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with momelotinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and momelotinib is a BCRP inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with momelotinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and momelotinib is a BCRP inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with momelotinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and momelotinib is a BCRP inhibitor.
Enasidenib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with enasidenib is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; enasidenib is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Encorafenib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with encorafenib is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; encorafenib is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Erythromycin: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with erythromycin is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; erythromycin is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Fostemsavir: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with fostemsavir is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; fostemsavir is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Glecaprevir; Pibrentasvir: (Moderate) Monitor for an increase in momelotinib and glecaprevir-related adverse reactions if coadministration is necessary. Concomitant use may increase the exposure of both medications. Momelotinib is an OATP1B1/3 substrate and BCRP inhibitor; glecaprevir is a BCRP substrate and an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%. (Moderate) Monitor for an increase in momelotinib and pibrentasvir-related adverse reactions if coadministration is necessary. Concomitant use may increase the exposure of both medications. Momelotinib is an OATP1B1/3 substrate and BCRP inhibitor; pibrentasvir is a BCRP substrate and an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with rifampin is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; rifampin is an OATP1B1/3 inhibitor. Coadministration increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Isoniazid, INH; Rifampin: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with rifampin is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; rifampin is an OATP1B1/3 inhibitor. Coadministration increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with momelotinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and momelotinib is a BCRP inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with clarithromycin is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; clarithromycin is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Leflunomide: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with leflunomide is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; leflunomide is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Leniolisib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with leniolisib is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; leniolisib is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Letermovir: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with letermovir is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; letermovir is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Pazopanib: (Major) Avoid coadministration of pazopanib and momelotinib due to the potential for increased pazopanib exposure. Pazopanib is a BCRP substrate; momelotinib is a BCRP inhibitor. Consider selection of an alternative concomitant medication with no or minimal potential to inhibit BCRP.
Rifampin: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with rifampin is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; rifampin is an OATP1B1/3 inhibitor. Coadministration increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Rosuvastatin: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with momelotinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and momelotinib is a BCRP inhibitor.
Rosuvastatin; Ezetimibe: (Moderate) Monitor for an increase in rosuvastatin-related adverse reactions, including myopathy and rhabdomyolysis, during concomitant use with momelotinib. Concurrent use may increase rosuvastatin exposure. Rosuvastatin is a BCRP substrate and momelotinib is a BCRP inhibitor.
Sofosbuvir; Velpatasvir: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with velpatasvir is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; velpatasvir is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with velpatasvir is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; velpatasvir is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%. (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with voxilaprevir is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; voxilaprevir is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of momelotinib is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a BCRP substrate and momelotinib is a BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with momelotinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and momelotinib is a BCRP inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with momelotinib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a BCRP substrate and momelotinib is a BCRP inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with momelotinib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a BCRP substrate and momelotinib is a BCRP inhibitor.
Teriflunomide: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with teriflunomide is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; teriflunomide is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Topotecan: (Major) Avoid coadministration of momelotinib with oral topotecan due to increased topotecan exposure; momelotinib may be administered with intravenous topotecan. Coadministration increases the risk of topotecan-related adverse reactions. Oral topotecan is a BCRP substrate and momelotinib is a BCRP inhibitor.
Trofinetide: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with trofinetide is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; trofinetide is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with momelotinib. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a BCRP substrate and momelotinib is a BCRP inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with clarithromycin is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; clarithromycin is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Momelotinib is a kinase inhibitor that inhibits wild type Janus Kinase 1 and 2 (JAK1/JAK2) and mutant JAK2V617F. This contributes to signaling of cytokines and growth factors that are important for hematopoiesis and immune function. Momelotinib and its major human circulating metabolite, M21, have higher inhibitory activity for JAK2 compared to JAK3 and tyrosine kinase 2 (TYK2). Additionally, momelotinib and M21 inhibit activin A receptor type 1 (ACVR1), also known as activin receptor like kinase 2 (ALK2), producing subsequent inhibition of liver hepcidin expression and increased iron availability, resulting in increased red blood cell production. Myelofibrosis is associated with dysregulated JAK signaling, which contributes to inflammation and ACVR1 hyperactivation. JAK signaling recruits and activates STAT (signal transducers and activation of transcription) proteins which result in nuclear localization and regulation of gene transcription.
Momelotinib is administered orally. It is approximately 91% plasma protein bound in healthy subjects. Its steady state apparent volume of distribution is 984 L (118%). Momelotinib is metabolized by multiple cytochrome P450 enzymes, including CYP3A4 (36%), CYP2C8 (19%), CYP2C9 (17%), CYP2C19 (19%), and CYP1A2 (9%). M21 is an active human metabolite that has approximately 40% of the pharmacological activity of momelotinib. M21 is formed by CYP followed by aldehyde oxidase metabolism of momelotinib. The mean M21 to momelotinib ratio for AUC ranged from 1.4 to 2.1. Following a single oral dose of radiolabeled momelotinib, 69% (13% unchanged) of radioactivity was excreted in feces and 28% (less than 1% unchanged) in urine. Approximately 12% of the administered dose was excreted in urine as M21. The elimination half-life of momelotinib and the M21 metabolite is 4 to 8 hours. Momelotinib clearance is 103 L/hour (87%). Momelotinib inhibited STAT3 phosphorylation in whole blood from patients with myelofibrosis; maximal inhibition occurred 2 hours after dosing and inhibition persisted for at least 6 hours. Circulating hepcidin was observed for the 24-week duration of momelotinib therapy in patients with myelofibrosis. Momelotinib did not prolong the QT interval at 4 times the highest recommended dosage of 200 mg.
Affected cytochrome P450 isoenzymes and drug transporters: OATP1B1/1B3, BCRP, CYP2B6, UGT1A1, UGT1A9, P-gp
Momelotinib is an OATP1B1/B3 substrate. Concomitant use with an OATP1B1/B3 inhibitor increases momelotinib Cmax and AUC, which may increase the risk of adverse reactions with momelotinib. Momelotinib is a BCRP inhibitor and may increase exposure of BCRP substrates and adverse reactions. The dosage of rosuvastatin, a BCRP substrate, should be initiated at 5 mg and not increased to more than 10 mg once daily when administered concomitantly with momelotinib. Momelotinib is a weak reversible, time-independent inhibitor of CYP2B6. Momelotinib is an inhibitor of UGT1A1 and UGT1A9. M21 is an inducer of UGT1A1. Momelotinib and M21 are substrates for P-gp.
-Route-Specific Pharmacokinetics
Oral Route
The momelotinib steady-state Cmax is 479 nanograms/mL (61%) and AUC is 3,288 nanograms x hour/mL (60%) at the maximum recommended dosage. Momelotinib Cmax and AUC increase dose proportionally from 100 mg to 300 mg (0.5 to 1.5 times the maximum recommended dosage), but less than dose-proportional from 400 mg to 800 mg (2 to 4 times the recommended dosage). There is no clinically significant accumulation. Median time to momelotinib Cmax at steady state is 2 hours post dose. Food had no clinically significant effect on momelotinib pharmacokinetics in healthy subjects following either a high-fat meal (800 kilocalorie; 50% fat) or low-fat meal (400 kilocalorie; 20% fat).
-Special Populations
Hepatic Impairment
Severe hepatic impairment (Child-Pugh C) increased momelotinib Cmax by 13% and AUC by 97%; the M21 metabolite Cmax decreased by 76% and AUC decreased by 48%. Mild or moderate hepatic impairment (Child-Pugh A or B) did not significantly affect momelotinib pharmacokinetics.
Renal Impairment
The pharmacokinetic profile was not significantly affected in renally impaired patients (eGFR: 16.4 mL/min/1.73 m2 to more than 120 mL/min/1.73 m2). The effect of end stage renal disease receiving dialysis on momelotinib pharmacokinetics is unknown.
Geriatric
Age (range, 28 to 92 years) has no clinically meaningful effect on the pharmacokinetic parameters of momelotinib.
Gender Differences
Gender has no clinically meaningful effect on the pharmacokinetic parameters of momelotinib.
Ethnic Differences
Ethnicity (83% White, 6% Asian, and 2% Black) has no clinically meaningful effect on the pharmacokinetic parameters of momelotinib.
Obesity
Weight (range, 34 to 138 kg) has no clinically meaningful effect on the pharmacokinetic parameters of momelotinib.